Therapeutic composition containing 4, 6-dimethyl-3-pyridazone and process of inducing hypnosis and tranquilization therewith



U it States THERAPEUTIC COMPOSITION CONTAINING 4,6-

DINIETHYL-S- AZONE AND PROCESS OF INDUCING HYPNOSIS AND TRANQUILIZATION THEREWITH Arnold Curtis Osterberg, Pearl River, N.Y., and Charles Edward Rauh HI, Bogota, N.J., assignors to American Cyanamid Company, New York, N.Y., a corporation of Maine No Drawing. Filed Mar. 14, 1960, Ser. No. 14,510

4 Claims. (Cl. 167-52) This invention relates to a new article of manufacture and to methods of using the same and more particularly is concerned with a therapeutic composition containing the compound 4,6-dimethyl-3-pyridazone in dosage unit form having central nervous system (CNS) depressant activity and to methods of inducing sleep and/ or hypnosis and/ or tranquilization in warm-blooded animals, including man.

Throughout history, compounds having hypnotic (sedative plus soporific) effects have been utilized to depress sensory and mental processes and to lower the perception of external stimuli thus inducing sleep. However, many of these compounds exert their effects for too short a period when small doses are administered and yet with increased dosage, progress too easily into general anesthesia, stupor and, eventually coma. Many of these compounds also exhibit undesirable characteristics such as unpleasant taste, production of irritation of the gastrointestinal tract, kidney damage, blood dyscrasias, cardiac and respiratory depression, and a drug tolerance which sometimes ends in physical dependence or in pathology due to cumulative effects.

The present invention provides a new hypnotic which is of medium long duration for those whose sleep is repeatedly interrupted due to physical or psychic reasons, in contradistinction to the shorter-duration type of hypnotic required by those who experience some difficulty in falling asleep initially but merely require that promotion of confidence and equanimity provided by a short-acting somnitacient.

4,6-dimethyl-3-pyridazone possesses valuable central nervous system (CNS) depressant properties as exemplified by hypnotic and tranquilizing effects. This compound has demonstrated its value in a number of tests and com pares favorably with such CNS depressant drugs as phenobarbital (a hypnotic agent) and meprobamate (a tranquilizing agent). Tests in animals such as mice, rats, rabbits, and dogs have determined the effect of 4,6-dimethyl-3-p-yridazone on ataxia, motor activity, reflexes such as the righting reflex, and lethality. These various tests show that this compound is intermediate in potency between phenobarbital and meprobamate. Reproduction of spontaneous motor activity is a valuable test for demo-nstrating tranquilizing action and 4,6-dimethyl-3-pyridazone is more effective than meprobamate in this respect. Phenobarbital does not show tranquilizing properties by this test. Furthermore, 4,6-dimethyl-3-pyridazone does not produce the initial undesirable excitant properties evident with both phenobarbital and meprobamatc.

Loss of the righting reflex at non-toxic doses may bev considered a desirable effect for hypnotic agents. While 4,6-dimethyl-3-pyridazone is not quite as potent as phenobarbital in this respect, it has demonstrated a Wider margin of safety as judged by the wide spread in doses required to produce hypnotic action and death. Furthermore, this compound shows a greater range of therapeutic usefulness than either phenobarbital or meprobamate as measured by the desirable large diflerence in doses required to produce ataxia and a loss of the righting reflex.

The new medicinal agent of this invention comprises dosage unit forms of 4,6-dimethyl-3-pyridazone, a known "ice chemical compound which may be prepared by methods well known in the chemical literature. The compound is a white solid which is only slightly soluble in water. Nevertheless it is readily absorbed by the body upon oral administration.

Extensive laboratory tests have established that 4,6- dimethyl-S-pyridazone is an effective hypnotic and tranquilizing agent of low toxicity.

The effective clinical dose of 4,6-dimethyl-3-pyridazone is from about milligrams to about 1000 milligrams.

It has also been found that 4,6-dimethyl-3-pyridazone has a potentiating effect on other drugs that depress the central nervous system, particularly the barbituates. A prolonged duration of the CNS depression is observed when 4,6-dimethyl-3-pyridazone is administered orally with or before an intraperitoneal injection of a sodium pentobarbital for example. Thus it has been found that oral doses of 200 mg./kg. of 4,6-dimethyl-3-pyridazone given prior to intraperitoneal doses of 50 mg./kg. of sodium pentobarbital, produce an 83 percent increase in sleep time over controls. Similar results may also be obtained when these compounds are given simultaneously.

The new, orally administrable compositions of this invention are particularly useful for the treatment of warm-blooded animals, including humans, when hypnosis or sedation or transquilization is desired. The drug may be administered in the form of tablets, capsules, powders or in a flavored oral suspension or in aqueous solution for parenteral use. The active ingredient 4,6-dimethy1- 3-pyridazone may be associated with a pharmaceutical carrier, diluent or the like which serves to present the material in a form which will render the composition particularly suitable for animal and human use. The pharmaceutical carrier, diluent, filler, extender, and/ or excipient may be either a solid or liquid material. Thus, the composi tions may take the form of capsules, tablets, powders, suspensions or other dosage forms which are particularly use ful for oral ingestion. For example, suitable solid car- 'riers, diluents and tableting adjuvants include lactose, cornstarch, talc, magnesium stearate, stearic acid, cellulose powders, gums, and the like. Alternatively, the pure compound may be administered in liquid form by using suitable liquid carriers, such as glycerine, oils, glycols, and so forth. In still another dosage form the active material may be compounded with flavoring materials and suspending agents such as acacia bentonite or carboxymethylcellulose in the preparation of an aqueous suspension which is particularly suitable for children and persons having difliculty in swallowing a tablet or capsule.

An important characteristic of 4,6-dimethyl-3-pyridazone is its low toxicity, having an oral LD in mice of 820 mg./kg. as compared to 255 mg./kg. for sodium phenobarbital. The hypnotic potency (HD in mice was found to be 320 mg./kg.

The invention will be described in greater detail in conjunction with the following specific examples.

Example 1 Mgms. 4,6-dimethyl-3-pyridazone 100 Lactose 25 The above ingredients were thoroughly mixed and placed in a hard gelatin capsule.

The above ingredients were thoroughly mixed and placed in a soft gelatin capsule.

3 Example 3 Mgms. 4,6-dimethyl-3-pyridazone 500 Talc 10 Starch 90 The above ingredients were thoroughly mixed, granulated using a 10 percent gelatin solution, and formed into a tablet.

The above composition provides an aqueous solution for parenteral use.

The method in accordance with this invention comprises administering internally the above described medicinal compositions to an animal and/or a human being to produce hypnotic or tranquilizing activity.

We claim:

1. An hypnotic and tranquilization preparation in dosage unit form comprising from about 100 to about 1000 milligrams of 4,6-dimethyl-3-pyridazone and a pharmaceutical carrier.

2. A composition according to claim 1 in which the dosage unit form is a tablet.

3. A composition according to claim 1 in which the dosage unit form is a capsule.

4. A method of inducing hypnosis and tranquilization in humans which comprises orally administering to a human being from about 100 milligrams to about 1000 milligrams of 4,6-dimethyl-3-pyridazone in dosage unit form and a pharmaceutical carrier therefor.

References Cited in the file of this patent UNITED STATES PATENTS 2,839,532 Druey et al June 17, 1958 OTHER REFERENCES Ajello et al.: C. A. 35, 1941, page 3643(7). 

4. A METHOD OF INDUCING HYPNOSIS AND TRANQUILIZATION IN HUMANS WHICH COMPRISES ORALLY ADMINISTERING TO A HUMAN BEING FROM ABOUT 100 MILLIGRAMS TO ABOUT 1000 MILLIGRAMS OF 4,6-DIMETHYL-3-PYRIDAZONE IN DOSAGE UNIT FORM AND A PHARMACEUTICAL CARRIER THEREFOR. 